The interaction of the lipase inhibitor orlistat with ethanol in healthy volunteers.

OBJECTIVES: The primary objective was to investigate the possible interference of ethanol on the orlistat effect on inhibition of dietary fat absorption and the possible interference of orlistat on the pharmacokinetics of ethanol. Secondary objectives were to assess the tolerability during concomitant dosing of orlistat and ethanol and to determine the ethanol effect on plasma levels of orlistat. METHODS: This was a double-blind, placebo-controlled, parallel, randomized study performed in 30 (three parallel groups of ten subjects each) healthy normal weight male subjects between the ages of 20 and 30 years. A 5-day run-in period to accustom subjects to a standardized diet of 2500 kcal/day (30% fat) and to establish baseline fecal fat excretion was followed by a 6-day treatment period. Subjects were randomly assigned to one of three treatment groups (A = orlistat 120 mg t.i.d. and ethanol placebo, B = orlistat 120 mg t.i.d. and 40 g ethanol qd on days -1 and 6, and 40 g bid on days 1-5, and C = orlistat placebo tid and 40 g ethanol qd on days -1 and 6, and 40 g b.i.d. on days 1 5). Serial blood samples were collected for determination of ethanol serum concentrations at specified times over 5 h after each dose of ethanol on days -1 and 6, and for determination of orlistat plasma concentrations on days 1, 3, 5, and 6. Feces were collected quantitatively on days -5 through 8 for analysis of fecal fat. RESULTS: The means of baseline-corrected fecal fat excretion values were comparable: 23.7 g for group A (orlistat) and 22.7 g for group B (orlistat and ethanol). No significant difference was found regarding ethanol pharmacokinetic parameters between treatments with orlistat and placebo. No apparent differences existed between the number of plasma samples with measurable orlistat concentrations in groups A and B. CONCLUSION: Concomitant ingestion of social amounts of ethanol did not alter the inhibitory effect of orlistat on dietary fat absorption during short-term treatment (6 days) with orlistat. Short-term treatment with orlistat had no significant influence on ethanol pharmacokinetics.

Role of lipase in the regulation of upper gastrointestinal function in humans.

The role of lipase in the regulation of upper gastrointestinal function is poorly understood. We studied the effect of orlistat, a new, potent, and highly specific lipase inhibitor, on gastric emptying, cholecystokinin (CCK) release, and pancreaticobiliary secretion. Three groups of studies were performed in nine healthy volunteers, using the double-indicator technique with a triple-lumen duodenal tube, polyethylene glycol 4000 as a duodenal perfusion marker, and 99mTc-diethylenetriamine pentaacetic acid as a meal marker. Gastric emptying, pancreaticobiliary output, and postprandial plasma CCK levels were measured after ingestion of the following isocaloric 500-ml liquid meals with or without 200 mg orlistat: 1) a pure fat meal (10% Intralipid), 2) a meal containing free fatty acids, or 3) an albumin-glucose meal. All experiments were performed in a randomized, placebo-controlled, crossover design. Orlistat markedly inhibited lipase activity in all three experiments. Orlistat given with the fat meal reduced CCK release and output of lipase, trypsin, and bilirubin and accelerated the rate of gastric emptying (P < 0.05). After ingestion of the free fatty acid or albumin-glucose meal, orlistat had no significant effect on any of these parameters. We conclude that lipase plays an important, nutrient-specific role in the regulation of gastric emptying and pancreaticobiliary secretion after ingestion of fatty meals in humans.

Lack of interaction between orlistat and oral contraceptives.

OBJECTIVES: Orlistat, a potent and selective inhibitor of gastrointestinal lipases, is designed for the treatment of obesity. A double-blind, randomised, placebo-controlled, 2-way crossover study investigated the possible influence of orlistat on the ovulation-suppressing action of combination oral contraceptives (OC). METHODS: After an 8-day run-in prior to the first of two consecutive menstrual cycles (Day 1 was the first day of menstruation), two groups of 10 healthy women, 20-27 years of age and on a stable regimen with OCs, received either 120 mg orlistat t.i.d. or placebo t.i.d. on Days 1-23 of the first cycle, and, separated by a placebo washout period on Days 24-28, the alternative treatment on Days 1-23 of the second cycle. In both cycles, serum luteinizing hormone (LH) was measured on Days 12-16 and progesterone on Days 12, 16, 19-23. RESULTS: The geometric means of time averaged concentrations (Days 12-16 for LH and Days 19-23 for progesterone) in the cycles with orlistat and placebo, respectively, and the one-sided 95% confidence region for the mean in the cycle with orlistat were 1.92, 2.03 and < 2.23 IU 1-1 for LH and 0.147, 0.145 and < 0.176 micrograms 1-1 for progesterone. The one-sided 95% confidence region for the ratio (orlistat/placebo) of geometric means was < 1.06 for LH and < 1.11 for progesterone. CONCLUSION: During normal ovulation the peak serum concentration of LH is above 30 IU 1-1 around Day 14 of the cycle, and that of progesterone exceeds 3 micrograms 1-1 around Day 21. The 95% confidence regions for the means, as well as all individual concentrations, were below these limits. It was concluded that orlistat did not influence the ovulation suppressing action of oral contraceptives.

PIP: In the Netherlands, a double-blind, randomized, placebo-controlled, two-way crossover study was conducted to determine whether administration of the inhibitor of gastrointestinal lipases, Orlistat, concomitantly with combined oral contraceptives (OCs) inhibits the ovulation-suppressing action of OCs. The 20 subjects, 20-27 years old, were healthy and had a body mass index between 22 and 27 kg m-2. All subjects completed the study. Most adverse events were mild and related to the pharmacological effect of Orlistat (fatty or oily stool, flatus with discharge, or abdominal pain). The geometric means of time-averaged serum concentrations in the cycles with Orlistat and the placebo and the 1-sided 95% confidence region for the mean in the cycle with Orlistat were 0.147, 0.145, and less than 0.176 mcg l-1 for progesterone and 1.92, 2.03, and less than 2.23 IU l-1 for luteinizing hormone (LH), respectively. These figures were well below the peak concentrations during normal ovulation (3 mcg l-1 for progesterone and 30 IU l-1 for LH). The plasma concentration of Orlistat was either close to the limit of quantification (1 mcg l-1) or below this limit. These findings suggest that Orlistat had no effect on the ovulation-suppression capabilities of the OCs.

Study on the possible interaction between tenoxicam and atenolol in hypertensive patients.

Sixteen hypertensive male out-patients (33-54 y), whose blood pressure (BP) had been normalized (diastolic BP < 90 mmHg) by treatment with a daily dose of 50 mg atenolol (CAS 29122-68-7), participated in this double-blind, placebo-controlled, parallel group study, which investigated the possible influence of the non-steroidal anti-inflammatory drug tenoxicam (CAS 59804-37-4) on the control of BP by atenolol. After a run-in of 10 days, to assess the stability of BP control by atenolol, and to determine baseline parameters, 8 patients in group A received 20 mg tenoxicam (2 x 20 mg on days 1 and 2), and 8 patients in group B received placebo, daily over 15 days (days 0-14), concomitantly with their atenolol regimen. BP was measured under standardized conditions on several days. Heart rate (EHR) after 5 min of exercise by bicycle ergometry (constant 75W), and parameters of renal function were assessed before (baseline) and during concomitant dosing of atenolol and tenoxicam. On day 14 the mean changes (delta A, delta B) from baseline of pre-dose BP (mmHg) and EHR (beats/min) in groups A and B, and the one-sided 95% confidence regions (R) for delta A, respectively, were (delta A, delta B, R): 4.4, 1.6, < 9.5 for sitting systolic BP, 2.8, -0.3, < 4.5 for sitting diastolic BP, -0.3, -0.6, < 5.5 for standing systolic BP, -0.6, -1.9, < 3.0 for standing diastolic BP, 0.4, -7.5, < 0.4 for EHR at pre-dose, 3.1, 0.6, < 7.8 for EHR at 3.5 h post-dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the inhibition of dietary fat absorption by full versus divided doses of orlistat.

Orlistat is a potent and selective inhibitor of gastrointestinal lipases. The drug is designed for the treatment of obesity. The effect on dietary fat absorption of orlistat after administration of divided doses spread over 2 hours from mid-meal, in comparison with that after administration of a full dose mid-meal, was investigated in a randomized, single-blind study including 16 hospitalized healthy males. After a 5-day run-in, to accustom the subjects to a diet of 2350 kcal and 76 g fat per day and to establish baseline fecal fat excretion, subjects received, in two parallel groups of eight over 8 days, three times a day 80 mg orlistat at mid-meal, and placebo at mid-meal and 0.5, 1, and 2 hr after mid-meal (group A), or placebo at mid-meal, and 20 mg orlistat at mid-meal and 0.5, 1, and 2 hr after mid-meal (group B). Feces were collected to measure total fat excretion. The mean (SD) of fecal fat in percent of dietary fat, after deduction of pretreatment fecal fat, was (%) 36.1 (4.2) and 37.0 (9.3) in groups A and B, respectively. Changing the mode of administration of orlistat, within the dose regimens investigated, does not affect its pharmacologic efficacy.

Influence of dietary composition on the inhibition of fat absorption by orlistat.

Orlistat, a potent and selective inhibitor of gastrointestinal lipases, is designed for the treatment of obesity. The effect of orlistat on dietary fat absorption, when it was administered with diets differing in fibre content (high and low) and accessibility of fat (intra- and extracellular fat), was investigated in 32 hospitalized healthy males, according to an open, two-factorial study design. The subjects were randomly allocated to one of four parallel groups of equal size: A = intracellular fat, high fibre (28 g/day); B = extracellular fat, high fibre; C = extracellular fat, low fibre (9 g/day); or D = intracellular fat, low fibre. After a 5-day run-in period to accustom the volunteers to the standardized diet (2500 kcal and 84 g fat per day) and to establish baseline faecal fat parameters, they received 80 mg orlistat, three times daily mid-way through each meal for 8 days. Faeces were collected to measure total fat and free fatty acid excretions. The mean baseline-corrected excretion (% of dietary fat) in groups A, B, C and D, respectively, was 37.0, 30.4, 30.3 and 34.5 for total fat, and 6.5, 4.3, 2.6 and 3.9 for free fatty acids. The 95% confidence intervals for the difference between the means for high fibre and low fibre groups and for intracellular fat and extracellular fat groups, respectively, were 1.4 +/- 4.9 and 5.5 +/- 4.9 for total fat, and 2.2 +/- 3.1 and 1.9 +/- 3.1 for free fatty acids. The statistically significant difference (P < 0.05) in total faecal fat between intracellular fat and extracellular fat groups, in absolute terms < 5 g fat/day, was not regarded as clinically relevant. Under the conditions of this study, dietary fibre content and accessibility of fat had no relevant effect on the inhibition of fat absorption by orlistat.

Effect of a novel beta-adrenoceptor agonist (Ro 40-2148) on resting energy expenditure in obese women.

The aim of this single-blind, placebo-controlled study was to investigate the effects of the new beta-adrenergic compound Ro 40-2148 on resting energy expenditure (REE) at rest and after an oral glucose load in non-diabetic obese women before and after two weeks of treatment. After one week of placebo administration and after an overnight fast and one hour rest, REE and glucose and lipid oxidation rates were measured by indirect calorimetry (hood system) before and for 6 h after a single dose of placebo solution. A 75 g oral glucose tolerance test (OGTT) was performed during this period starting 90 min after the placebo administration. During the following two weeks, using a randomization design, six patients received Ro 40-2148 at a dose of 400 mg diluted in 100 ml water twice a day (i.e. 800 mg per day), while six others continued with the placebo administration. The same tests and measurements were repeated after two weeks, except for the treatment group which received the drug instead of the placebo. The 14-day period of drug administration did not increase REE measured in post-absorptive conditions. Similarly, there was no acute effect on REE of a 400 mg dose of Ro 40-2148. In contrast, glucose-induced thermogenesis was significantly increased after two weeks in the treatment group (means +/- s.e.m.: 3.7 +/- 1.3%, P = 0.047), while no change was observed in the placebo group (-0.8 +/- 0.7%, not significant). Since there was no significant change in the respiratory quotient, the increase in energy expenditure observed in the treatment group was due to stimulation of both lipid and glucose oxidation. The drug induced no variations in heart rate, blood pressure, axillary temperature or in plasma glucose, insulin and free fatty acid levels. In conclusion, this study shows that Ro 40-2148 activates glucose-induced thermogenesis in obese non-diabetic patients.

Effect on dietary fat absorption of orlistat, administered at different times relative to meal intake.

Orlistat (O) is a potent and selective inhibitor of gastrointestinal lipases. The effect on dietary fat absorption following dosing of O at different times relative to meals was investigated in a placebo (P) controlled study in 24 hospitalized healthy males. After a 5-day run-in, to accustom the subjects to a diet of 2400 kcal and 77 g fat per day and to establish baseline faecal fat excretion, subjects received, in four parallel groups of 6. over 8 days three times daily doses of 80 mg O.P.P (group A) or P. 80 mg O.P (group B) or P.P. 80 mg O (group C) or P.P.P (group D) at mid-meal. 1 h and 2 h after mid-meal respectively. Faeces were collected to measure total fat excretion. The mean (s.d.) of faecal fat in percent of dietary fat, after deduction of pre-treatment faecal fat, was (%) 32.8 (8.1), 34.0 (8.8), 26.9 (4.0) and -1.4 (1.7) in groups A. B. C and D respectively. It was concluded that, within the time period investigated, the pharmacological effect of O is not critically dependent on the time of dosing relative to meals.